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Chapter 4 Carbohydrate Metabolism

Chapter 4 Carbohydrate Metabolism. 牛永东. 生物化学的学习方法. 特点一：与数理化不同，尚未进入 定量科学 的阶段，还处在 定性科学 阶段。因此不可能通过公式或定理推出一个准确的结论 特点二： 是没有绝对，几乎所有的结论都可以被一些例外打破（生物多样性） 一般性结论：生物化学的学习应以概念为主 --- 以 记忆 为主，在记忆的基础上 加以理解. 【 目的与要求 】.

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Chapter 4 Carbohydrate Metabolism

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  1. Chapter 4 Carbohydrate Metabolism 牛永东

  2. 生物化学的学习方法 特点一：与数理化不同，尚未进入定量科学的阶段，还处在定性科学阶段。因此不可能通过公式或定理推出一个准确的结论 特点二： 是没有绝对，几乎所有的结论都可以被一些例外打破（生物多样性） 一般性结论：生物化学的学习应以概念为主---以记忆为主，在记忆的基础上加以理解

  3. 【目的与要求】 • 掌握糖酵解glycolysis 、有氧氧化、巴斯德效应Pastuer effect、磷酸戊糖途径 、磷酸戊糖途径、糖异生gluconeogenesis、乳酸循环Cori cycle 等概念…… • 掌握糖酵解、有氧氧化(TCA cycle)、磷酸戊糖途径、糖异生、糖原合成glycogenesis与分解glycogenolysis的细胞定位、过程、关键酶、调节及意义…… • 掌握血糖的来源和去路及其调节……

  4. outline • Introduction • Glycolysis (Anaerobic Degradation) • Aerobic oxidation of glucose • The Pentose Phosphate Pathway • Glycogen Formation and Degradation • Gluconeogenesis

  5. CATABOLISM ANABOLISM Definition of Metabolism • Metabolism (Greek for change) : all the chemical and physical processes that take place in the body * Synthesis (anabolism): AGlucose – Glycogen A FA+ Glycerol – TG A Amino Acids – Protein ARequires Energy Macromolecules * Breakdown (catabolism): A Glycogen – Glucose A TG – Fatty Acids + Glycerol A Protein – Amino Acids AEnergy is released Small molecules

  6. 1. What are Carbohydrates? • Carbohydrates are aldehyde or ketone compounds with multiple hydroxyl groups • Empirical formula = (CH2O)n, literally a “carbon hydrate” • CHO make up 3% of the body’s organic matter

  7. Functions of CHO • Energy Source(66.8 kJ/1g carbohydrate) • Structural elements • Component of nucleic acids • Conversion to lipids and non-essential amino acids • …….

  8. Categories of Carbohydrates • Monosaccharides (Single sugar units): the smallest carbohydrates ,serve as fuel and carbon sources • Disaccharides(formed from 2 monosaccharides joined by a glycoside linkage) • Polysaccharides: many monosaccharide units (starch, cellulose)

  9. Monosaccharides • Glucose (C6H12O6) -found in fruits, vegetables, honey -“blood sugar” -used for energy • Fructose - Found in fruits, honey, corn syrup -“fruit sugar” • Galactose - Found as part of lactose in milk • Glucose (C6H12O6)

  10. Disaccharides • Sucrose = glucose + fructose (brown sugar;25% of sugar intake) • Lactose = glucose + galactose (milk sugar; least sweet) • Maltose = glucose + glucose (honey) Natural Sweetness Sucrose Maltose

  11. CH OH 6 2 O H H Glucose 1 H 4 O H H H O O H H O H CH2OH O O -[1-6] linkage O O O CH2OH CH2OH CH2OH CH2 O O O O O O O O -[1-4] linkages Polysaccharides starch CH2OH

  12. Section 1Digestion of carbohydrates Brush Border of the Mucosal Epithelium Mouth BLOOD stomach 1 maltose Starch a -amylase glucose Salivary amylase Pancreatic amylase Glycogen 2 sucrose fructose lactose 3 galactose galactose Monosaccharides glucose fructose no significant digestive enzymes present limited breakdown of starch and glycogen occurs Responsible for most of carbohydrate digestion

  13. Glucose Glucose Glucose Galactose Galactose Galactose GLUT-2 + Na Glucose Galactose Fructose; also glucose, Na+ SGLT-1 GLUT-5 Intestinal Epithelial cell Lumen ofintestine Brush border Na+ Fructose Na+ 2K+ ATP 3Na+ 2K+ ADP + Pi 2K+ 3Na+ 3Na+ 2K+ to capillaries = facilitated diffusion = Na,K-ATPase + = Na - dependent co-transport Na+ dependent glucose Absorption andtransporter,SGLT

  14. Family of glucose transporters Name Tissue location Km Comments GLUT1 All mammalian tissues 1mmol/L Basal glucose uptake GLUT2 Liver and pancreatic 15~20mmol/L In the pancreas,plays a role  cells in regulation of insulin In the liver, removes excess glucose from the blood GLUT3 All mammalian tissues 1mmol/L Basal glucose uptake GLUT4 Muscle and fat cells 5mmol/L Amount in muscle plasma membrane increases with endurance training GLUT5 Small intestine － Primarily a fructose transporter

  15. Not digested: Dietary Fiber • Water insoluble fibers - Cellulose, hemicellulose , pectins （果胶）…… • Water soluble fiber - beans, rice, carrots, fruits…… - Obesity, diabetes, cancer…… • Recommended intake of fiber • 20-35 g/day; insoluble:soluble = 3:1

  16. 3. Overview of carbohydrate metabolism l y c o g e n P i G - 6 - 6 - p h o s p h o g l u c o n a t e P P i P e n t o s e p h o s p h a t e p a t h w a y F r u c t o s e 6 - p n o n - c a r b o h y d r a t e s t r i o s e s p h o s p h a t e G l u c o n e o g e n e s i s p y r u v a t e l a c t a t e a c e t y l C o A T r i c a r b o x y l i c a c i d c y c l e e n e r g y C O + H O + Glycogen G l y c o g e n e s i s G o l y s i s U D P G G - 1 - P glucose Anaerobic degradation (glycolysis) Aerobic oxidation 2 2

  17. Section 2 Glycolysis (Anaerobic Degradation) • “Glycolysis” is derived from Greek words glycos (sugar, sweet) and lysis (dissolution) • The glycolytic pathway (Glucose to pyruvate) was elucidated by 1940, largely through the pioneering contributions of GustavEmbden.so glycolysis is also known as the Embden-Meyerhof pathway

  18. Glycolysis • Where in cell ? • What are the inputs ? • What are the outcomes ? • Oxygen required ?

  19. Glycolysis （糖酵解） • For glycolysis, the overall goal is to break the glucose molecule into smaller, more oxidized pieces • 11 steps metabolic pathway to convert 6 carbon glucose into 2 molecules of 3 carbon lactate 乳酸and two molecules each of and ATP • Occurs in cytoplasm • glycolysis hastwo stages: glycolytic pathway (Glucose to pyruvate); Fermentation（发酵）phase (pyruvate to lactate) • Anaerobic • Does not REQUIRE oxygen • Occurs whether oxygen is available or not

  20. glycolytic pathway = breakdown of glucose to yield energy and pyruvate breakage of C3-C4 bond

  21. glycolytic pathway hastwo phases A. Energy investment phase (Reactions, 1-5) Glucose(6C) is first phophorylated (thus activated) and then cleaved to produce two glyceraldehyde-3-phosphate(3C) intermediates. 2 ATPs are invested. (the preparatory phase) B.Energy payoff phase (Reactions 6-10) two glyceraldehyde 3-phosphate intermediatesare oxidized, generating to two pyruvate plus four ATP molecules

  22. CH2 OH CHO C=O H-C-OH HO-C-H H-C-OH H-C-OH glucose CH2 O H O O O -P-O -P-O -P-O OH OH OH Energy investment phase isomerase Step 1. Hexokinase (1 ATP utilization) Step 2. Phosphoglucose Isomerase (PGI) Step 3. Phosphofructokinase -1 (PFK-1) (2 ATP utilization)

  23. CH2OPO3= C=O CH2O CH2 OH CHO CH2OH C=O C=O H-C-OH HO-C-H HO-C-H H-C-OH DHAP H-C-OH H H-C-OH H-C-OH C H2 OH HC=O + O O O O CH2O H-C-OH -P-O -P-O -P-O -P-O CH2OPO3= OH OH OH OH Glyceraldehyde 3-PO4 energy investmentphase dihydroxyacetone phosphate 4. Aldolase

  24. energy investmentphase dihydroxyacetone phosphate Glyceraldehyde 3-PO4 TPI isomerase The isomerization of an aldose to a ketose 5. Triose Phosphate Isomerase (TIM or TPI )

  25. energy investmentphase Glucose ATP Hexokinase ADP Glucose 6-phosphate Phosphogluco- isomerase Fructose 6-phosphate ATP Phosphofructokinase ADP Fructose 1.6-bisphosphate Uses 2 ATP Aldolase Glyceraldehyde 3-phosphate Dihydroxyacetone phosphate Triose phosphate isomerase

  26. O COO PO4 ~OPO3 H-C-OH C CHO ADP ATP NAD+ CH2OPO3 H-C-OH H-C-OH NADH CH2OPO3 CH2OPO3 +H+ Energy payoff phase (Reactions, 6-10) Phosphoglycerate kinase Glyceraldehyde-3-PO4 dehydrogenase

  27. COO C~ OPO3 -H2O CH2 COO COO COO 3-PGA Pyruvate H-C-OH H-C-OPO3 C=O ADP 2-PGA PEP ATP CH2OPO3 CH2OH CH3 Energy payoff phase High energy Low energy

  28. Glyceraldehyde 3-phosphate NAD+ + Pi Oxidation NADH + H+ ATP generation ATP generation Pyruvate Glyceraldehyde 3-phosphate dehydrogenase 1,3-Bisphosphoglycerate ADP Phosphoglycerate kinase ATP 3-Phosphoglycerate Phosphoglyceromutase 2-Phosphoglycerate Enolase H2O Phosphoenolpyruvate ADP Pyruvate kinase ATP energy payoffphase

  29. Overview of glycolytic pathway

  30. Summary of Energy Relationships for glycolytic pathway * Input = 2 ATP 1. glucose + ATP  glucose-6-P 2. fructose-6-P + ATP  fructose 1,6 bisphosphate * Output = 4 ATP + 2 NADH 1. 2 glyceraldehyde-3-P + 2 Pi + 2 NAD+ 2 (1,3 bisphosphoglycerate) + 2 NADH 2. 2 (1,3 bisphosphoglycerate) + 2 ADP 2 (3-P-glycerate) + 2 ATP 3. 2 PEP + 2 ADP  2 pyruvate + 2 ATP *Net = 2 ATP and 2 NADH

  31. Pyruvate Anaerobic Glycolysis Alcohol Fermentation Aerobic Glycolysis Fate of Pyruvate • Two anerobic pathways: (Low O2 )  - to lactate via lactate dehydrogenase in muscle - to ethanol(fermentation) via ethanol dehydrogenase • Aerobic pathway – through citric acid cycle and respiration; Enough O2,this pathway yields far more energy NADH + O2 NAD+ + energy Pyruvate + O2 3CO2 + energy Oxygen availability determines fate of Pyruvate

  32. The anaerobic fate of Pyruvate ( Reaction 11 of glycolysis ) • Hydrogen at C4 of NADH is transferred to the pyruvate • uses up all the NADH (reducing equivalents) produced in glycolysis

  33. Energy Yield From Glycolysis Overall process of anaerobic glycolysis in muscle can be represented: • glucose 6 CO2 = -2840 kJ/mol • 2 ATPs produced = 61 kJ/mol glucose • Energy yield = 61/2840 = 2% in all: high investment, low output The lactate, the end product, is exported from the muscle cell and carried by the blood to the liver, where it is reconverted to glucose

  34. Summary of Glycolysis • 11 steps ; Location: cytosol • Original material: glucose (C6H12O6) • End product: lactate • - Twice substrate level phosphorylations • - Net of 2 ATP • d. Key enzymes: Hexokinase (HK) …….energy investmentphase • Phosphofructokinase 1 (PFK-1) …….energy investmentphase • Pyruvate kinase (PK) …….energy payoffphase • e. Once dehydrogenation: oxidation • Once hydrogenation: reduction • No oxygen is required

  35.   FBP-2 PFK-2 active inactive P P FBP-2 PFK-2 inactive active － － －     The regulation of glycolysis Hormone regulation Covalent regulation Allosteric regulation ATP Glucagon Adenylate cyclase AMP Citrate cAMP ADP Glucose ATP Glucose 6-phosphate ATP F-6-P F-2,6-BP Phosphoprotein Phosphatase PKA ADP Pi glycolysis ATP PFK-1 Pi ADP Lactate F-1,6-BP AMP Citrate

  36. 3. The significance of glycolysis • Glycolysis is the emergency energy-yielding pathway, such as play ball, climb mountain.….. • Glycolysis is the major way to produce ATP in some tissues, even though the oxygen supply is sufficient, such as RBC, retina, testis, skin……

  37. Section 3 Aerobic oxidation of glucose • The process of oxidation completely from glucose to CO2 and H2O is named aerobic oxidation • This process is the major process to provide energy for most tissues

  38. TCA cycle 3 phases of Glucose Aerobic oxidation 1.Oxidation from glucose to pyruvate in cytosol (6C to 3C) 2. Oxidation frompyruvate to acetyl CoAin mitochondria(3C to 2C) 3.Tricarboxylic acid cycleand oxidative phosphorylation (2C to 1C) O2 O2 H2O O2 Acetyl CoA H+ +e Glucose G-6-P CO2 Pyruvate Pyruvate cytosol mitochondria

  39. O C O C o A O - C C H C H 3 3 S O C 2. Oxidation from pyruvate to acetyl CoA (3C to 2C) NADH Pyruvate DH complex CoASH NAD+ Acetyl-CoA: a common two-carbon unit Pyruvate+NAD++HSCoA Acetyl CoA+NADH+H++CO2

  40. Pyruvate dehydrogenase complex E1. pyruvate dehydrogenase （丙酮酸脱氢酶） E2. dihydrolipoyl transacetylase （二氢硫辛酰胺转乙酰酶） E3. dihydrolipoyl dehydrogenase （二氢硫辛酰胺脱氢酶）

  41. TPP E1 FAD E3 E2 Pyruvate dehydrogenase complex

  42. 3. Two stages of the 3rd phase of Glucose Aerobic oxidation • Stage I The acetyl-CoA is completely oxidized into CO2, with electrons collected by NAD and FAD via a cyclic pathway (tricarboxylic acid cycle) • Stage II Electrons of NADH and FADH2 are transferred to O2 via a series carriers, producing H2O and a H+ gradient, which will promote ATP formation （oxidative phosphorylation） (NEXT CHAPTER)

  43. Tricarboxylic acid cycle (2C to 1C) • Citric Acid Cycle or Krebs cycle • Occurs in mitochondrial matrix • Is the biochemical hub of the cell, oxidizing carbon fuels, usually in the form of acetyl CoA, interconversion of carbohydrates, lipids, and some aminoacids, as well as serving as a source of precursors for biosynthesis • For the citric acid cycle, the goal is to use the oxidative power of O2 to derive as much energy as possible from the products of glycolysis

  44. C2 NADH+H+ CO2 NADH+H+ FADH2 NADH+H+ CO2 GTP Substrates required: Oxaloacetic Acid GDP 3NAD+ FAD two-carbon units (Acetyl-CoA) Intermediate Reactants: Citric Acid Each Acetyl-CoA yields 2 CO2, 3 NADH + H+, 1 FADH2, 1 GTP Output: Oxaloacetic AcidGTP 3 NADH FADH22CO2 (4 high-energy electrons) C6 C4 Tricarboxylic acid cycle C5 C4

  45. S O C o A O - C O C3 C H 3 O C H O 2 O C C H O C C2 O - O - C H C H 2 2 C C1 - O O - O O Stage ITricarboxylic acid cycle CoASH 2C Citrate synthase ＋ 6 C 4C Citrate Oxaloacetic Acid

  46. O - O - O C3 C O O C H O H C 2 C 2 O - H O C C2 C O - C H C 2 O H C C1 - O O - O Aconitase cis-aconitate intermediate 6 C 6 C

  47. O - O - O O C C C O 2 C H C H O 2 2 H C C C H 2 O - C C O HO O C O C - O - O Isocitrate DH NAD NADH 5 C 6 C a-ketoglutarate Isocitrate

  48. O - O O - C O O 2 C C C H 2 C H 2 C H 2 C H 2 C O C O O C C o A S - O a-ketoglutarate DH NAD+, CoASH NADH 5 C 4 C Succinyl CoA a-ketoglutarate

  49. O - O - O O C C C H C H 2 2 C H C H 2 2 C C O O - O C o A S CoASH SuccinylCoA synthetase GTP GDP, Pi 4C 4C Succinyl CoA

  50. O O - O C C O - H C C H 2 C C H 2 H O C C O - O O - (FADH2) (FAD) 4C 4C fumarate

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